Advertisement

Drug Metabolism in Liver Failure

  • Simon W. Lam
Chapter

Introduction

The liver is involved in the metabolism and elimination of many medications entering the body and liver disease leads to widespread alterations in drug pharmacokinetics and pharmacodynamics. An understanding of physiologic changes during liver disease and their corresponding effects on drug disposition will be useful for clinicians to optimize therapy and avoid adverse reactions. This chapter describes the complex relationship between drug properties and drug metabolism in liver failure. In addition, it will illustrate the effects of liver failure on the metabolism of specific classes of medications that are frequently used in anesthesiology and critical care such as sedatives, opioids, and neuromuscular blocking agents.

Pharmacokinetics (PK) and Pharmacodynamics (PD)

Any medication entering the body follows a unique process: absorption , distribution, metabolism, and elimination. This process ultimately determines how much drug is available at the targeted site...

Keywords

Cytochrome P450 Glucuronidation Oxidation Half-life Metabolism Pharmacokinetics Pharmacodynamics Liver failure Sedatives Opioids Neuromuscular blockade 

Abbreviations

PK

Pharmacokinetics

PD

Pharmacodynamics

Clh

Hepatic clearance

Eh

Hepatic extraction

Clint

Intrinsic clearance

Fu

Fraction unbound

Q

Hepatic blood flow

Vd

Volume of distribution

CYP

Cytochrome

GABA

Gamma-aminobutyric acid

t1/2

Half-life

AUC

Area-under-the-curve

Cmax

Maximum concentration

References

  1. 1.
    Rodighiero V. Effects of liver disease on pharmacokinetics. An update. Clin Pharmacokinet. 1999;37(5):399–431.CrossRefPubMedGoogle Scholar
  2. 2.
    Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol. 2008;64(12):1147–61.CrossRefPubMedGoogle Scholar
  3. 3.
    Morgan DJ, McLean AJ. Clinical pharmacokinetic and pharmacodynamic considerations in patients with liver disease. An update. Clin Pharmacokinet. 1995;29(5):370–91.CrossRefPubMedGoogle Scholar
  4. 4.
    Delco F, Tchambaz L, Schlienger R, Drewe J, Krahenbuhl S. Dose adjustment in patients with liver disease. Drug Saf. 2005;28(6):529–45.CrossRefPubMedGoogle Scholar
  5. 5.
    Kalaitzakis E. Gastrointestinal dysfunction in liver cirrhosis. World J Gastroenterol. 2014;20(40):14686–95.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ohkubo H, Okuda K, Iida S, Ohnishi K, Ikawa S, Makino I. Role of portal and splenic vein shunts and impaired hepatic extraction in the elevated serum bile acids in liver cirrhosis. Gastroenterology. 1984;86(3):514–20.PubMedGoogle Scholar
  7. 7.
    Verbeeck RK, Horsmans Y. Effect of hepatic insufficiency on pharmacokinetics and drug dosing. Pharm World Sci. 1998;20(5):183–92.CrossRefGoogle Scholar
  8. 8.
    Westphal JF, Brogard JM. Drug administration in chronic liver disease. Drug Saf. 1997;17(1):47–73.CrossRefPubMedGoogle Scholar
  9. 9.
    Caujolle B, Ballet F, Poupon R. Relationship among beta-adrenergic blockade, propranolol concentration, and liver function in patients with cirrhosis. Scand J Gastroenterol. 1988;23(8):925–30.CrossRefPubMedGoogle Scholar
  10. 10.
    Gerbes AL, Remien J, Jungst D, Sauerbruch T, Paumgartner G. Evidence for down-regulation of beta-2-adrenoceptors in cirrhotic patients with severe ascites. Lancet. 1986;1(8495):1409–11.CrossRefPubMedGoogle Scholar
  11. 11.
    Janku I, Perlik F, Tkaczykova M, Brodanova M. Disposition kinetics and concentration-effect relationship of metipranolol in patients with cirrhosis and healthy subjects. Eur J Clin Pharmacol. 1992;42(3):337–40.CrossRefPubMedGoogle Scholar
  12. 12.
    Dao MT, Villeneuve JP. Kinetics and dynamics of triamterene at steady-state in patients with cirrhosis. Clin Invest Med. 1988;11(1):6–9.Google Scholar
  13. 13.
    Marcantonio LA, Auld WH, Murdoch WR, Purohit R, Skellern GG, Howes CA. The pharmacokinetics and pharmacodynamics of the diuretic bumetanide in hepatic and renal disease. Br J Clin Pharmacol. 1983;15(2):245–52.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Schwartz S, Brater DC, Pound D, Green PK, Kramer WG, Rudy D. Bioavailability, pharmacokinetics, and pharmacodynamics of torsemide in patients with cirrhosis. Clin Pharmacol Ther. 1993;54(1):90–7.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Villeneuve JP, Verbeeck RK, Wilkinson GR, Branch RA. Furosemide kinetics and dynamics in patients with cirrhosis. Clin Pharmacol Ther. 1986;40(1):14–20.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Bakti G, Fisch HU, Karlaganis G, Minder C, Bircher J. Mechanism of the excessive sedative response of cirrhotics to benzodiazepines: model experiments with triazolam. Hepatology. 1987;7(4):629–38.CrossRefGoogle Scholar
  17. 17.
    Davis M. Cholestasis and endogenous opioids: liver disease and exogenous opioid pharmacokinetics. Clin Pharmacokinet. 2007;46(10):825–50.CrossRefGoogle Scholar
  18. 18.
    MacGilchrist AJ, Birnie GG, Cook A, Scobie G, Murray T, Watkinson G, et al. Pharmacokinetics and pharmacodynamics of intravenous midazolam in patients with severe alcoholic cirrhosis. Gut. 1986;27(2):190–5.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg. 1973;60(8):646–9.CrossRefGoogle Scholar
  20. 20.
    Trouvin JH, Farinotti R, Haberer JP, Servin F, Chauvin M, Duvaldestin P. Pharmacokinetics of midazolam in anaesthetized cirrhotic patients. Br J Anaesth. 1988;60(7):762–7.CrossRefPubMedGoogle Scholar
  21. 21.
    Kraus JW, Desmond PV, Marshall JP, Johnson RF, Schenker S, Wilkinson GR. Effects of aging and liver disease on disposition of lorazepam. Clin Pharmacol Ther. 1978;24(4):411–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Morgan DJ, Campbell GA, Crankshaw DP. Pharmacokinetics of propofol when given by intravenous infusion. Br J Clin Pharmacol. 1990;30(1):144–8.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Servin F, Cockshott ID, Farinotti R, Haberer JP, Winckler C, Desmonts JM. Pharmacokinetics of propofol infusions in patients with cirrhosis. Br J Anaesth. 1990;65(2):177–83.CrossRefPubMedGoogle Scholar
  24. 24.
    Valitalo PA, Ahtola-Satila T, Wighton A, Sarapohja T, Pohjanjousi P, Garratt C. Population pharmacokinetics of dexmedetomidine in critically ill patients. Clin Drug Investig. 2013;33(8):579–87.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Karol MD, Maze M. Pharmacokinetics and interaction pharmacodynamics of dexmedetomidine in humans. Best Pract Res Clin Anaesthesiol. 2000;14:261–9.CrossRefGoogle Scholar
  26. 26.
    Viby-Mogensen J, Hanel HK. Prolonged apnoea after suxamethonium: an analysis of the first 225 cases reported to the Danish Cholinesterase Research Unit. Acta Anaesthesiol Scand. 1978;22(4):371–80.CrossRefPubMedGoogle Scholar
  27. 27.
    Donati F. Onset of action of relaxants. Can J Anaesth. 1988;35(3 Pt 2):S52–8.CrossRefPubMedGoogle Scholar
  28. 28.
    Khalil M, D’Honneur G, Duvaldestin P, Slavov V, De Hys C, Gomeni R. Pharmacokinetics and pharmacodynamics of rocuronium in patients with cirrhosis. Anesthesiology. 1994;80(6):1241–7.CrossRefPubMedGoogle Scholar
  29. 29.
    Ward ME, Adu-Gyamfi Y, Strunin L. Althesin and pancuronium in chronic liver disease. Br J Anaesth. 1975;47(11):1199–204.CrossRefPubMedGoogle Scholar
  30. 30.
    Hunter JM, Parker CJ, Bell CF, Jones RS, Utting JE. The use of different doses of vecuronium in patients with liver dysfunction. Br J Anaesth. 1985;57(8):758–64.CrossRefPubMedGoogle Scholar
  31. 31.
    Craig RG, Hunter JM. Neuromuscular blocking drugs and their antagonists in patients with organ disease. Anaesthesia. 2009;64(Suppl 1):55–65.CrossRefPubMedGoogle Scholar
  32. 32.
    Fujita A, Ishibe N, Yoshihara T, Ohashi J, Makino H, Ikeda M, et al. Rapid reversal of neuromuscular blockade by sugammadex after continuous infusion of rocuronium in patients with liver dysfunction undergoing hepatic surgery. Acta Anaesthesiol Taiwanica. 2014;52(2):54–8.CrossRefGoogle Scholar
  33. 33.
    Keating GM. Sugammadex: a review of neuromuscular blockade reversal. Drugs. 2016;76(10):1041–52.CrossRefPubMedGoogle Scholar
  34. 34.
    Tegeder I, Lotsch J, Geisslinger G. Pharmacokinetics of opioids in liver disease. Clin Pharmacokinet. 1999;37(1):17–40.CrossRefGoogle Scholar
  35. 35.
    Ferrier C, Marty J, Bouffard Y, Haberer JP, Levron JC, Duvaldestin P. Alfentanil pharmacokinetics in patients with cirrhosis. Anesthesiology. 1985;62(4):480–4.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Curran MP, Robins GW, Scott LJ, Perry CM. Alvimopan. Drugs. 2008;68(14):2011–9.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Garnock-Jones KP, McKeage K. Methylnaltrexone. Drugs. 2010;70(7):919–28.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Cleveland ClinicClevelandUSA

Personalised recommendations